J. Org. Chem. 1996, 61, 3897-3899
Butane 2,3-Bisacetal Protection of Vicinal Diequatorial Diols Jean-Luc Montchamp, Feng Tian, Matthew E. Hart, and J. W. Frost* Department of Chemistry, Michigan State University, East Lansing, Michigan 48824-1322 Received January 29, 1996
Selective hydroxyl group protection in polyhydroxy molecules continues to be a challenge in synthetic chemistry.1 For example, methods for selective protection of vicinal diequatorial diols are rare. Ley and coworkers have introduced two very useful protecting groups which exploit multiple anomeric effects to accomplish this task. Diol reaction with 3,3′,4,4′-tetrahydro-6,6′-spirobi-2H-pyran (bis-DHP) to give a dispiroacetal (Dispoke)2 and diol reaction with 1,1,2,2-tetramethoxycyclohexane (TMC) affording a cyclohexane 1,2diacetal (CDA)3 have been successfully applied to a variety of carbohydrates and polyhydroxylated molecules. However, bis-DHP is of limited utility for large-scale work due to the synthetic steps required for its preparation.2b TMC is readily prepared from cyclohexane-1,2-dione, although this starting material is relatively expensive. An additional practical difficulty is the need for chromatographic purification of both bis-DHP and TMC.2b,3 In response to the requirements imposed by large-scale synthetic manipulations, reaction of vicinal diequatorial diols with 2,2,3,3-tetramethoxybutane (TMB) to afford butane 2,3-bisacetal (BBA) protection has been examined. As part of efforts directed toward the synthesis of 3-dehydroquinate (DHQ) synthase inhibitors,4 the C-3,4 diequatorial hydroxyls of quinic acid needed to be selectively protected. Previous protection of these hydroxyl groups had been achieved in two ways. Knowles and coworkers protected the C-3,4 diequatorial diol unit in 20% yield by direct reaction of methyl quinate with benzyl chloromethyl ether (BOMCl).5 Formation of multiple products resulted in low yields and required a tedious purification to obtain the desired product. Another approach by Tisne`s and co-workers utilized O-stannylene derivatives as part of a protection-deprotection sequence also involving the axial C-5 hydroxyl group.6 Neither of these strategies nor the aforementioned Dispoke or CDA protecting groups seemed amenable to our need for gramscale quantities of final products and the multistep syntheses required to synthesize these DHQ synthase inhibitors. It occurred to us that TMB would be an inexpensive alternative to TMC while retaining the desired vicinal diequatorial diol protection selectivity. TMB has apparently not been reported in the literature, although the monoacetal 3,3-dimethoxybutan-2-one7 (1) (a) Ziegler, T. Angew. Chem., Int. Ed. Engl. 1994, 33, 2272. (b) Greene, T. W.; Wuts, P. G. M. Protective Groups in Organic Chemistry, 2nd ed.; Wiley: New York, 1991. (2) (a) Ley, S. V.; Woods, M.; Zanotti-Gerosa, A. Synthesis 1992, 52. (b) Ley, S. V.; Leslie, R.; Tiffin, P. D.; Woods, M. Tetrahedron Lett. 1992, 33, 4767. (c) Ley, S. V.; Boons, G.-J.; Leslie, R.; Woods, M.; Hollinshead, D. M. Synthesis 1993, 689. (3) Ley, S. V.; Priepke, H. W. M.; Warriner, S. L. Angew. Chem., Int. Ed. Engl. 1994, 33, 2290. (4) Tian, F.; Montchamp, J.-L.; Frost, J. W. Unpublished results. (5) Bender, S. L.; Widlanski, T.; Knowles, J. R. Biochemistry 1989, 28, 7560. (6) Chahoua, L.; Baltas, M.; Gorrichon, L.; Tisne`s, P.; Zedde, C. J. Org. Chem. 1992, 57, 5798. (7) Braude, E. A.; Timmons, C. J. J. Chem. Soc. 1953, 3131.
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and the bisethylene glycol acetal cis-1,6-dimethyl-2,5,7,10-tetraoxabicyclo[4.4.0]decane8 have been known for some time. Protection of diethyl tartrate diol with monoacetal 3,3-dimethoxybutan-2-one has recently been reported.9 TMB reagent was prepared by refluxing a methanol solution of trimethyl orthoformate and 2,3butanedione with a few drops of sulfuric acid followed by purification of the crude product using distillation. The experimental advantages of purification by distillation and the ability to employ an inexpensive starting material became apparent during the preparation of TMB in 50-60% yield on hundred-gram scale. Selective protection of the C-3,4 vicinal diequatorial hydroxyls of methyl quinate as butane 2,3-bisacetals utilized reaction conditions similar to those employed for CDA protection. A methanolic solution of quinate ester was refluxed with TMB in the presence of trimethyl orthoformate and catalytic (()-10-camphorsulfonic acid for 12-18 h. The desired BBA-protected methyl quinate was obtained in excellent yield. Fifty grams of quinic acid were then routinely converted into the crystalline BBA-protected methyl quinate as a one-pot procedure in over 80% yield (Table 1, entry 1). The BBA protecting group is compatible with a wide variety of reagents and can be deprotected with aqueous trifluoroacetic acid in methylene chloride.4 The scope of BBA protection has been extended beyond quinic acid (Table 1). Reaction of myo-inositol with 2 equiv of TMB used the conditions previously described for methyl quinate protection. A pure, crystalline product precipitated out of the solution. This material displayed a simple NMR spectrum which could only be attributed to the highly symmetrical diprotected meso compound (Table 1, entry 2). The yield of meso-diBBA inositol derivative improved with longer reaction times. At relatively short reaction times, low yields of meso-diBBA product were obtained along with a complex mixture of other components. The inositol protection pattern observed for BBA has previously been obtained during reaction of inositol with 1,3-dichloro-1,1,3,3-tetraisopropyldisiloxane (TIPSCl).10 While this silyl protecting group has found some applications in inositol chemistry, the cost of TIPSCl limits its use. BBA provides the same protection pattern in higher yield and at a much lower cost. Reaction of TMB with carbohydrates provided an additional test of the scope of BBA protection. In general, BBA protection was observed to display selectivities similar to those previously observed for CDA and Dispoke protection.3 TMB reaction with methyl R-D-glucopyranoside gave an inseparable, equimolar mixture of 2,3- and 3,4-regioisomers (Table 1, entry 3). BBA protection of methyl R-D-galactopyranoside gave the desired product along with a small amount of its anomer (Table 1, entry 4). For the methyl pyranosides of D-mannose (Table 1, entry 5), D-lyxose (Table 1, entry 6), L-rhamnose (Table 1, entry 7), and 2-deoxy-D-glucose (Table 1, entry 8) TMB proved to be consistently selective for vicinal diequatorial diol protection. Overall, the BBA protecting group appears to be a practical alternative to CDA or Dispoke for selective (8) Fuchs, B.; Goldberg, I.; Shmueli, U. J. Chem. Soc., Perkin Trans. 2 1972, 357. (9) Berens, U.; Leckel, D.; Oepen, S. C. J. Org. Chem. 1995, 60, 8204. (10) Watanabe, Y.; Mitani, M.; Morita, T.; Ozaki, S. J. Chem. Soc., Chem. Commun. 1989, 482.
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J. Org. Chem., Vol. 61, No. 11, 1996
Notes
Table 1. Butane 2,3-Bisacetal Protection of Carbocycles and Carbohydrates
protection of vicinal diequatorial diols. BBA-protected compounds appear to usually be crystalline materials. A useful advantage over other protecting groups is the simple NMR spectrum of the BBA group. Unlike the cyclohexyl resonances that characterize CDA or Dispoke, BBA displays only singlets which are very diagnostic and minimize overlap with other resonances. The rigidity resulting from the formation of the 2,3-dimethoxy-2,3dimethyl-1,4-dioxane moiety also provides an element for conformational control that can be exploited in subsequent reactions.4 Finally, the inexpensive, large-scale preparation of TMB and the reagent’s convenient puri-
fication by distillation makes BBA protection a particularly appealing option for large-scale synthetic manipulations. Experimental Section General Chemistry. See ref 11 for general experimental information. Melting points were uncorrected and were determined using a Mel-Temp II melting point apparatus. For NMR spectra in pyridine-d5, the 1H NMR spectrum was referenced to internal TMS (δ ) 0.00 ppm), and the 13C NMR spectrum was (11) Montchamp, J.-L.; Frost, J. W. J. Org. Chem. 1994, 59, 7596.
Notes referenced to pyridine-d5 with the center of the middle triplet at δ ) 135.5 ppm. 2,2,3,3-Tetramethoxybutane. 2,3-Butanedione (68.0 mL, 0.775 mol), trimethyl orthoformate (200 mL, 1.83 mol), and MeOH (100 mL) were treated with sulfuric acid (7 drops). The resulting solution was refluxed 20 h under Ar, during which time the solution turned dark brown. Powdered NaHCO3 (2.2 g) was added to the cool reaction mixture. Concentration under reduced pressure afforded an orange liquid which was diluted with ether and washed with saturated aqueous NaHCO3 (2×). A clear yellow liquid was obtained after concentration. Although this material is impure, it can be used directly for the protection reaction. This material was however routinely distilled to afford a colorless liquid (73 g, 53%): bp 32-33 °C (0.8 mmHg); bp 172174 °C (760 mmHg); 1H NMR (CDCl3) δ 3.31 (s, 12 H), 1.32 (s, 6 H); 13C NMR (CDCl3) δ 103.0, 49.3, 19.0. Anal. Calcd for C8H18O4: C, 53.91; H, 10.18. Found: C, 54.01; H, 10.08. Quinic Acid Protection (Entry 1). A suspension of quinic acid (47.5 g, 0.247 mol) and Dowex 50 H+ (10 g) in MeOH (350 mL) was refluxed under Ar for 15 h. Heating was stopped, and the mixture was filtered to remove the acid catalyst which can be reused directly in subsequent runs. The filter was washed with MeOH (2 × 25 mL). To the combined filtrates were added trimethyl orthoformate (125 mL, 1.14 mol), 2,2,3,3-tetramethoxybutane (44.8 g, 0.251 mol), and (()-10-camphorsulfonic acid (2.22 g, 0.010 mol). The resulting solution was refluxed under Ar for 22 h. The resulting dark brown solution was treated with powdered NaHCO3 (8.9 g). Concentration afforded an orange suspension which was partitioned between EtOAc and saturated aqueous NaHCO3. The aqueous layer was reextracted once with EtOAc and the combined organic layers were dried over MgSO4. Filtration through silica and concentration afforded an orange oil which started to crystallize. Addition of EtOAc/hexane (1:5, v/v) caused complete crystallization into a single block. Recrystallization (EtOAc and hexane) afforded a white solid (63.9 g, 81%). The brown mother liquor was purified by flash chromatography (EtOAc) to afford an additional amount of product (4.9 g, 6%) as a white foamy solid: mp (crystals) 139.8-140.2 °C; 1H NMR (CDCl ) δ 4.31 (ddd, J ) 12, 10, 5 Hz, 1 H), 4.19 (ddd, 3 J ) 3, 3, 3 Hz, 1 H), 3.79 (s, 3 H), 3.60 (dd, 10, 3 Hz, 1 H), 3.26 (2 s, 2 × 3 H), 2.19 (ddd, J ) 15, 3, 3 Hz, 1 H), 2.10 (ddd, J ) 12, 5, 3 Hz, 1 H), 2.03 (dd, J ) 15, 3 Hz, 1 H), 1.92 (dd, J ) 12, 12 Hz, 1 H), 1.34 (s, 3 H), 1.30 (s, 3 H); 13C NMR (CDCl3) δ 174.1, 100.2, 99.6, 75.7, 72.6, 69.0, 62.3, 52.8, 47.8, 38.5, 37.3, 17.7, 17.5. Anal. Calcd for C14H24O8: C, 52.49; H, 7.55. Found: C, 52.56; H, 7.52. Inositol Protection (Entry 2). A suspension of myo-inositol (0.591 g, 3.28 mmol) in methanol (10 mL), 2,2,3,3-tetramethoxybutane (1.19 g, 6.66 mmol), and trimethyl orthoformate (2.9 mL, 26.50 mmol) was treated with CSA (0.042 g, 0.18 mmol). The resulting mixture was refluxed under Ar. A white precipitate appeared slowly over time. After 135 h at reflux, heating was stopped and the cool reaction mixture was filtered. The precipitate was washed with EtOAc/hexane (1:1, v/v). Drying under vacuum afforded the diprotected product (1.05 g, 79%) as a white solid: mp > 330 °C; 1H NMR (C5D5N) δ 4.80 (dd, J ) 10, 9 Hz, 2, H), 4.71 (t, J ) 2 Hz, 1 H), 4.28 (t, J ) 9 Hz, 1 H), 4.16 (dd, J ) 10, 2 Hz, 2 H), 3.34 (s, 6 H), 3.24 (s, 6 H), 1.45 (s, 6 H), 1.44 (s, 6 H); 13C NMR (C5D5N) δ 100.1, 99.5, 71.0, 70.9, 70.0, 69.5, 47.7, 47.6, 18.1, 18.0; HRMS (FAB) calcd for C18H32O10 (M - H+) 407.1917, found 407.1912. Anal. Calcd for C18H32O10: C, 52.93; H, 7.90. Found: C, 52.98; H, 7.90. General Procedure for BBA Protection. A suspension of diol (2-5 mmol, 1 equiv) in a solution of 2,2,3,3-tetramethoxybutane (1-1.2 equiv), trimethyl orthoformate (4 equiv) in methanol (2-5 mL/mmol of diol) was treated with camphorsulfonic acid (0.05 equiv). The mixture was refluxed under Ar for 12-18 h. The cool reaction mixture was then treated with powdered NaHCO3 (ca. 0.5 g) and concentrated under reduced pressure. Purification by flash chromatography or radial chromatography (eluent EtOAc and hexane) provided the protected carbohydrates.
J. Org. Chem., Vol. 61, No. 11, 1996 3899 Glucose protection (entry 3): 1H NMR (CDCl3) δ 4.80 (d, J ) 4 Hz, 1 H), 4.74 (d, J ) 4 Hz, 1 H), 3.60-4.00 (m, 12 H), 3.43 (s, 3 H), 3.41 (s, 3 H), 3.30 (s, 3 H), 3.29 (s, 3 H), 3.26 (s, 6 H), 3.06 (br, 4 H), 1.34 (s, 3 H), 1.33 (s, 3 H), 1.31 (s, 3 H), 1.29 (s, 3 H); 13C NMR (CDCl3) δ 99.6, 99.4 (2), 99.3, 99.2, 97.8, 71.7, 69.8, 69.6, 69.5, 69.2, 68.0, 67.4, 65.6, 61.4, 60.7, 55.0, 54.8, 47.8, 47.7 (2), 47.6, 17.5 (2), 17.4 (2); HRMS (FAB) calcd for C13H24O8 (M - H+) 307.1393, found 307.1401. Anal. Calcd for C13H24O8‚1/2H2O: C, 49.20; H, 7.94. Found: C, 49.29; H, 7.82. Galactose protection (entry 4): Mp 88-91 °C; 1H NMR (CDCl3) δ 4.84 (d, J ) 2 Hz, 1 H), 4.20 (dd, J ) 10, 3 Hz, 1 H), 4.05-4.10 (m, 1 H), 3.80-4.00 (m, 5 H), 3.43 (s, 3 H), 3.26 (s, 3 H), 3.25 (s, 3 H), 2.77 (br, 2 H), 1.34 (s, 3 H), 1.31 (s, 3 H); 13C NMR (CDCl3) δ 100.1, 98.3 (2), 70.1, 69.0, 66.1, 65.0, 62.6, 55.1, 47.9 (2), 17.7, 17.6; HRMS (FAB) calcd for C13H24O8 (M - H+) 307.1393, found 307.1380. Anal. Calcd for C13H24O8.1/2H2O: C, 49.20; H, 7.94. Found: C, 49.37; H, 7.98. Spectral data for the β-anomer: 1H NMR (CDCl3) δ 4.42 (d, J ) 8 Hz, 1 H), 3.804.05 (m, 6 H), 3.74 (dd, J ) 10, 3 Hz, 1 H), 3.55 (s, 3 H), 3.28 (s, 3 H), 3.27 (s, 3 H), 2.73, (br, 2 H), 1.33 (s, 3 H), 1.32 (s, 3 H); 13C NMR (CDCl3) δ 101.9, 100.1, 99.7, 74.9, 70.2, 68.0, 66.8, 62.1, 56.7, 48.0, 47.9, 17.6, 17.5. Mannose protection (entry 5): 1H NMR (CDCl3) δ 4.75 (s, 1 H), 4.11 (dd, J ) 10, 10 Hz, 1 H), 4.00 (dd, J ) 10, 3 Hz, 1 H), 3.93 (s, 1 H), 3.70-3.85 (m, 3 H), 3.37 (s, 3 H), 3.28 (s, 3 H), 3.26 (s, 3 H), 3.07 (s, 1 H), 2.49 (br, 1 H), 1.32 (s, 3 H), 1.29 (s, 3 H); 13C NMR (CDCl3) δ 101.0, 100.2, 99.7, 70.5, 69.5, 68.0, 62.7, 61.1, 54.8, 48.0, 47.8, 17.7, 17.6; HRMS (FAB) calcd for C13H24O8 (M - H+) 307.1393, found 307.1404. Anal. Calcd for C13H24O8: C, 50.64; H, 7.85. Found: C, 50.41; H, 7.90. Lyxose protection (entry 6): mp 63-64 °C; 1H NMR (CDCl3) δ 4.68 (s, 1 H), 4.05-4.25 (m, 1 H), 3.90-3.95 (m, 2 H), 3.55-3.70 (m, 2 H), 3.37 (s, 3 H), 3.27 (s, 3 H), 3.26 (s, 3 H), 2.82 (br, 1 H), 1.33 (s, 3 H), 1.28 (s, 3 H); 13C NMR (CDCl3) δ 101.1, 100.4, 99.6, 69.5, 68.6, 62.7, 60.4, 54.8, 47.9, 47.8, 17.6 (2); HRMS (FAB) calcd for C12H22O7 (M - H+) 277.1287, found 277.1296. Anal. Calcd for C12H22O7: C, 51.79; H, 7.97. Found: C, 51.50; H, 7.84. Rhamnose protection (entry 7): mp 144-147 °C; 1H NMR (CDCl3) δ 4.67 (s, 1 H), 3.90-4.00 (m, 2 H), 3.65-3.85 (m, 2 H), 3.36 (s, 3 H), 3.27 (s, 3 H), 3.24 (s, 3 H), 2.53 (br, 1 H), 1.32 (s, 3 H), 1.29 (s, 3 H), 1.28 (d, J ) 6 Hz, 3 H); 13C NMR (CDCl3) δ 100.8, 100.1, 99.7, 69.7, 68.3, 68.2, 66.3, 54.6, 48.0, 47.6, 17.7, 17.6, 16.5; HRMS (FAB) calcd for C13H24O7 (M - H+) 291.1444, found 291.1435. Anal. Calcd for C13H24O7: C, 53.41; H, 8.27. Found: C, 53.33; H, 8.25. 2-Deoxy glucose protection (entry 8): 1H NMR (CDCl3) δ 4.84 (d, J ) 3 Hz, 1 H), 4.12 (ddd, J ) 13, 10, 5 Hz, 1 H), 3.703.85 (m, 3 H), 3.62 (dd, J ) 10, 10 Hz, 1 H), 3.32 (s, 3 H), 3.28 (s, 3 H), 3.27 (s, 3 H), 2.37 (br, 1 H), 1.99 (dd, J ) 13, 5 Hz, 1 H), 1.77 (ddd, J ) 13, 13, 3 Hz, 1 H), 1.29 (s, 6 H); 13C NMR (CDCl3) δ 99.6, 99.5, 98.6, 69.9, 68.2, 64.6, 61.1, 53.4, 47.8, 47.6, 34.4, 17.6, 17.5. Anal. Calcd for C13H24O7: C, 53.41; H, 8.27. Found: C, 53.23; H, 8.22.
Acknowledgment. Research was supported by a grant from the National Institutes of Health. Mass spectral data were obtained at the Michigan State University Mass Spectrometry Facility which is supported, in part, by a grant (DRR-00480) from the Biotechnology Research Technology Program, National Center for Research Resources, National Institutes of Health. The NMR data were obtained on instrumentation that was purchased in part with funds from NIH (1-S10-RR04750) and NSF (CHE-88-00770 and 92-13241). JO960170N
